Maternal-Fetal Conflict: The Effect of Imprinted Genes on Fetal Growth

母胎冲突：印记基因对胎儿生长的影响

• 批准号: 7728220
• 负责人: RONALD M ADKINS
• 金额: $ 35.81万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7728220
• 关键词: Affect; Alleles; Animal Model; Barker Hypothesis; Birth Weight; Cardiovascular Diseases; Chronic Disease; Clinical; Conflict (Psychology); CpG dinucleotide; Cytosine; DNA; DNA Methylation; DNA Sequence; Development; Diabetes Mellitus; Dietary Intervention; Dietary intake; Disease; Enzymes; Epigenetic Process; Ethnic Origin; Exclusion Criteria; Exhibits; Fathers; Female; Fetal Growth; Fetus; Funding; Gene Expression Regulation; Genes; Genetic; Genome; Genomic Imprinting; Genomics; Goals; Growth; Health; Human; Hypertension; Illness impact; Individual; Inherited; Intake; Intervention; Life; Longevity; Low Birth Weight Infant; Medical; Metabolic Pathway; Methylation; Mothers; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutritional; Obesity; Parents; Pathway interactions; Pattern; Play; Pregnancy; Process; Public Health; Regulation; Research; Risk; Role; Silver-Russell syndrome; Single Nucleotide Polymorphism; Small for Gestational Age Infant; Surveys; Testing; Tissues; Triad Acrylic Resin; Variant; base; cost; design; disorder risk; enzyme activity; epigenetic variation; fetal; genetic risk factor; imprint; maternal-fetal conflict; methyl group; mortality; mouse model; next generation; offspring; parental influence; trait

Individuals born small for gestational age have increased risks of serious illness as newborns and throughout life, including hypertension, cardiovascular disease, type 2 diabetes and pregnancy-related hypertension and diabetes. Both traditional genetics and epigenetics play a major role in fetal growth regulation. Genes that are imprinted, meaning that either the maternally- or paternally-inherited allele is silenced in some or all tissues, have a large influence on the regulation of fetal growth. Indeed, it is thought that selection has led to the uniform pattern among imprinted genes that the paternal allele of growth- retarding loci and the maternal allele of growth-promoting loci are imprinted (silenced). One of the main mechanisms for imprinting a locus is the extensive addition of methyl groups to CpG dinucleotides on one of the parental alleles. Based on observations in model organisms, the extent of methylation of fetal DNA can be dramatically influenced by the mother's intake of nutrients involved in that metabolic pathway. The immediate goal of this research is to identify genetic (fetal, maternal, and parent-of-origin) and epigenetic influences on fetal growth. The ultimate goals are to be able to anticipate those fetuses that are predisposed to being small for gestational age and to determine how to reduce that risk with medical, nutritional, or pharmacological interventions. Objectives: In all imprinted regions of the genome, survey patterns of variation in DNA sequence (single nucleotide polymorphisms; SNPs) in 500 mother-father-newborn trios and DNA methylation in those newborns and determine the maternal intake of nutrients essential to DNA methylation during pregnancy. Hypotheses: 1) Variation in birth weight is due to a) direct maternal, b) direct fetal and/or c) parent-of- origin (imprinting) genetic effects. 2) Variation in birth weight is associated with patterns of DNA methylation in imprinted genes. 3) Variation in DNA methylation patterns is correlated with variation in maternal intake of nutrients key to that process. Design: DNA is being collected from 500 sets of mothers, fathers, and their newborns based on stringent inclusion/exclusion criteria. Both tagging SNPs and those previously associated with obesity- related traits in imprinted genomic regions will be surveyed. Across all imprinted genomic regions DNA methylation patterns will be determined in differentially methylated regions and imprinting control regions. Dietary survey instruments during pregnancy and just afterwards will be used to determine the maternal intake of nutrients vital to DNA methylation. Statistical analyses will be performed to test the three hypotheses.

胎龄小的人有严重的风险 疾病是新生儿和一生，包括高血压，心血管 疾病，2型糖尿病和与妊娠有关的高血压和糖尿病。两个都 传统的遗传学和表观遗传学在胎儿生长调节中起主要作用。 印记的基因，这意味着在母亲或 在某些或所有组织中，亲属关系的等位基因被沉默，具有较大的 对胎儿生长调节的影响。确实，人们认为选择 导致了印迹基因的统一模式，该基因的父亲等位基因 增长 - 智障基因座和促进生长基因座的母亲等位基因是 印刷（沉默）。印刷一个基因座的主要机制之一是 在其中一个父母的CPG二核苷酸中广泛添加甲基 等位基因。基于模型生物的观察结果， 胎儿DNA可能会受到母亲摄入养分的巨大影响 参与该代谢途径。这项研究的直接目标是 鉴定遗传（胎儿，母体和父母的遗传）和表观遗传影响 关于胎儿生长。最终目标是能够预见那些胎儿 易于对胎龄很小，并确定如何减少 医疗，营养或药理干预措施的风险。目标： 在基因组的所有印迹区域中，DNA序列变异的调查模式 （单核苷酸多态性； SNP）在500个母亲 - 纽伯恩三重奏和DNA中 这些新生儿中的甲基化并确定营养的产妇摄入量 怀孕期间DNA甲基化必不可少的。假设：1）出生变化 重量是由于a）直接母体，b）直接胎儿和/或c）父母的父母。 （印迹）遗传效应。 2）出生体重的变化与 印迹基因中DNA甲基化的模式。 3）DNA甲基化的变化 模式与孕产妇摄入养分的变化相关 过程。设计：正在从500套母亲，父亲及其 基于严格的包容/排除标准的新生儿。两者都标记SNP和 那些与肥胖基因组中与肥胖相关的特征相关的人 地区将进行调查。在所有印迹基因组区域中DNA甲基化 模式将在差异甲基化区域确定和印记 控制区域。怀孕期间和之后的饮食调查工具 将用于确定对DNA甲基化至关重要的营养摄入量。 将进行统计分析以检验这三个假设。